Effect of Local Injection of Lidocaine and Articaine plus Epinephrine on Methemoglobin Level during General Anesthesia

Statement of the Problem: Methemoglobinemia is a potentially life-threatening rare medical condition, which refers to an increase in the level of oxidized form of hemoglobin (methemoglobin). Excessive replacement of hemoglobin with methemoglobin leads to functional hypoxia and even fatal conditions. Purpose: The aim of this study was to evaluate the effect of two common local anesthetic agents namely lidocaine and articaine administered for hemostasis during surgery on methemoglobin level. Materials and Method: This prospective cohort study was conducted from January 2017 to December 2019. Demographic data including age, gender, and weight of patients were collected. Sixty patients were randomly divided into three groups (n=20) regarding the local anesthetic agent administered for hemostasis during surgery as lidocaine group (group 1), articaine group (group 2), and control group (no local anesthetic; group 3). The patients were candidates for orthognathic surgery, reconstruction of the maxillary and mandibular atrophic ridges with autogenous grafts, and reconstruction of maxillofacial fractures. The methemoglobin level was measured before surgery and six hours after the initiation of surgery. Results: The mean age and weight of patients were not significantly different among the three groups (p= 0.891 and p= 0.416, respectively). No significant differences were observed among the three groups regarding the gender distribution (p= 0.343) or type of surgery (p= 0.990). Statistical analysis did not show any significant difference in the mean baseline methemoglobin level among the three groups (p= 0.109). Although the mean methemoglobin values increased in the three groups, paired sample t-test did not show any significant change in the values at six hours after the initiation of surgery compared with baseline in any of the three groups (p= 0.083 for group 1, p= 0.096 for group 2, and p= 0.104 for group 3). Conclusion: The results demonstrated that administration of lidocaine and articaine plus epinephrine for hemostasis during general anesthesia are equally safe.


Introduction
Methemoglobinemia is a rare medical condition, which is potentially life threatening especially when it is not recognized and treated early [1]. Methemoglobinemia refers to an increase in the level of oxidized form of hemoglobin (methemoglobin). It may be either congeni-tal due to an abnormality in the hemoglobin structure or methemoglobin reductase enzyme, or acquired secondary to consumption of chemicals and drugs that oxidize hemoglobin [1][2][3]. Moreover, there are some reports regarding methemoglobinemia following conditions such as gastrointestinal infections, sepsis, and sickle cell crisis, which are highly uncommon conditions [1][2][3].
The oxidized form of hemoglobin (ferric form) cannot properly bind to oxygen, and excessive replacement of hemoglobin with methemoglobin leads to functional hypoxia [4]. The upper normal limit of methemoglobin is 1.5% and when it rises, patients develop a variety of signs and symptoms from mild to severe and lifethreatening conditions. Mild conditions are accompanied by cyanosis, dizziness, shortness of breath, cough, low blood oxygen saturation, and brown color arterial blood samples [5][6][7]. When the methemoglobin level exceeds 55%, patients experience unconsciousness and lethargy. Higher levels of methemoglobin (>70%) cause neurological and cardiac failure and could be fatal [5][6][7].
As mentioned earlier, acquired methemoglobinemia occurs in some patients following their exposure to some chemicals or drugs. Local anesthetic agents are among the medications that contribute to methemoglobinemia when administered for local anesthesia in conscious patients or for regional blocks and hemostasis during general anesthesia [2][3]8]. Local anesthetic agents in dentistry and oral and maxillofacial surgery are administered both for local anesthesia and hemostasis. A review of the published reports regarding methemoglobinemia related to local anesthetic agents named benzocaine, prilocaine, and lidocaine as the top three local anesthetic agents causing methemoglobinemia with a prevalence of 66%, 28% and 5%, respectively.
Data also demonstrated that most of the cases occurred outside of the operating room [3,8]. There are much fewer cases regarding articaine and methemoglobinemia [1]. Lidocaine and articaine plus epinephrine are two common local anesthetic agents administered for hemostasis during surgery. Because of the uncommon nature of methemoglobinemia and the need for its early management, early detection of this condition and the potential risk of its development are imperative by dentists or surgeons who administer oxidizing agents.
The aim of this study was to evaluate the effect of these two agents on methemoglobin level.

Materials and Method
This prospective cohort study was conducted in the Department of Oral and Maxillofacial Surgery of Taleghani Hospital between January 2017 and December 2019.
Patients >12 years of age that weighed >32 Kg, had no systemic disease (ASA I and II), and were candidates for orthognathic surgery, reconstruction of the maxillary and mandibular atrophic ridges with autogenous grafts, and reconstruction of maxillofacial fractures were included in this study. The exclusion criteria were congenital methemoglobinemia, pre-existing coronary artery disease, peripheral vascular disease, cerebrovascular diseases, sepsis, respiratory diseases, acidosis, anemia and glucose-6-phosphate dehydrogenase deficiency.
The objective and design of the study were completely explained to all participants and they were requested to read and sign the informed consent form. Statistical analyses were performed using SPSS version 23 (SPSS Inc., IL, USA). One-way ANOVA was used to compare the mean age, weight and baseline methemoglobin value among the three groups. The Chisquare test was used to compare gender distribution and type of surgery among the three groups. Paired sample t-test was used to compare methemoglobin changes dur-

Results
Sixty patients in three groups were evaluated in this study (n=20 in each group). Table 1

Discussion
High levels of methemoglobin are usually well-tolerated by healthy individuals, but very high concentrations or concurrence with compromised cardiopulmonary reserve can lead to rapid toxicity [1,4]. The acquired methemoglobinemia is much more common than the he-   In our study, we evaluated the top two most com- there is a general agreement regarding the clinically tolerable methemoglobin levels following lidocaine administration [2,5,14].

Conclusion
Within the limitations of this study, the results demonstrated that administration of lidocaine or articaine plus epinephrine for hemostasis in oral and maxillofacial surgeries was not associated with any increase in methemoglobin level and these agents are equally safe for administration during general anesthesia.

Conflicts of Interest
None